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Preclinical models suggest anticancer activity of IM156, a novel biguanide mitochondrial protein complex 1 inhibitor of oxidative phosphorylation (OXPHOS). This first-in-human dose-escalation study enrolled patients with refractory advanced solid tumors to determine the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D). Eligible patients received oral IM156 every other day (QOD) or daily (QD) and were assessed for safety, dose-limiting toxicities (DLTs), pharmacokinetics, and preliminary signals of efficacy. 22 patients with advanced cancers (gastric, n = 8; colorectal, n = 3; ovarian, n = 3; other, n = 8) received IM156 100 to 1,200 mg either QOD or QD. There were no DLTs. However, 1,200 mg QD was not well tolerated due to nausea; 800 mg QD was determined as the RP2D. The most frequent treatment-related AEs (TRAEs) were nausea (n = 15; 68%), diarrhea (n = 10; 46%), emesis (n = 9; 41%), fatigue (n = 4; 18%) and abdominal pain, constipation, and blood lactate increased (n = 2 each; 9%). Grade 3 nausea (n = 3; 14%) was the only grade ≥ 3 TRAE. Plasma exposures increased dose proportionally; mean Day 27 area under the curve (AUC0-24) values were higher following QD administration compared to the respective QOD regimen. Stable disease (SD), observed in 7 (32%) patients (confirmed in 2 [9%]), was the best response. To our knowledge, this is the first phase 1 study of an OXPHOS inhibitor that established a RP2D for further clinical development in cancer. Observed AEs of IM156 were manageable and SD was the best response.

Background The aim of the study is to evaluate the risk factors of anastomotic leakage (AL) and develop a nomogram to predict the risk of AL in surgical management of primary ovarian cancer. Methods We retrospectively reviewed 770 patients with primary ovarian cancer who underwent surgical resection of the rectosigmoid colon as part of cytoreductive surgery between January 2000 to December 2020. AL was defined based on radiologic studies or sigmoidoscopy with relevant clinical findings. Logistic regression analyses were performed to identify the risk factor of AL, and a nomogram was developed based on the multivariable analysis. The bootstrapped-concordance index was used for internal validation of the nomogram, and calibration plots were constructed. Results The incidence of AL after resection of the rectosigmoid colon was 4.2% (32/770). Diabetes (OR 3.79; 95% CI, 1.31–12.69; p = 0.031), co-operation with distal pancreatectomy (OR, 4.8150; 95% CI, 1.35–17.10; p = 0.015), macroscopic residual tumor (OR, 7.43; 95% CI, 3.24–17.07; p = 0https://ALnomogram.github.io/. Conclusion Four risk factors for AL after resection of the rectosigmoid colon are identified from the largest ovarian cancer study cohort. The nomogram from this information provides a numerical risk probability of AL, which could be used in preoperative counseling with patients and intraoperative decision for accompanying surgical procedures and prophylactic use of ileostomy or colostomy to minimize the risk of postoperative leakage. Trial registration Retrospectively registered.

Carcinoembryonic antigen (CEA) is the most widely used tumor marker in metastatic colorectal cancer (mCRC). However, its potential as a predictive marker of progression in mCRC during systemic chemotherapy, particularly in patients receiving monoclonal antibodies as a combination therapy, has remained of interest. Herein, we investigated whether CEA changes could predict disease progression and clinical outcomes in patients with mCRC cotreated with systemic chemotherapy and/or biologic agents. A total of 1261 patients with mCRC undergoing a first-line systemic treatment were included in this retrospective study. We analyzed the optimal cut-off value for CEA changes to predict progression at the first response evaluation by the treatment arm (chemotherapy alone, chemotherapy plus anti-vascular endothelial growth factor (VEGF) monoclonal antibody [mAb], and chemotherapy plus anti-epidermal growth factor receptor [EGFR] mAb). These cut-off values were then used to predict overall survival (OS) and progression-free survival (PFS). When stratified by their treatment arm, 891 (70.6%), 266 (21.0%), and 104 (8.2%) of the study patients were included in the chemotherapy alone-, anti-VEGF mAb, and anti-EGFR mAb groups, respectively. The optimal CEA cut-off values were 16.5% and 38.9% increase in the whole cohort and anti-EGFR mAb group, respectively, and these values showed high sensitivity and specificity for predicting disease progression. The patients in the entire population and anti-EGFR mAb group with CEA changes below these cut-off values showed significantly better OS and PFS outcomes compared those whose changes were above cut-off values. Among the patients with mCRC treated with anti-VEGF mAb, no associations were found between OS or PFS outcomes and CEA changes. CEA is potentially a good surrogate marker for predicting disease progression and survival outcomes in patients with mCRC receiving first-line systemic chemotherapy alone or chemotherapy with anti-EGFR mAb, whereas it is less effective in those treated with anti-VEGF mAb.

BACKGROUND: Bone marrow-derived mesenchymal stem cells (BMSCs) and bone morphogenetic protein-2 (BMP-2) have been studied for bone repair because they have regenerative potential to differentiate into osteoblasts. The development of injectable and in situ three-dimensional (3D) scaffolds to proliferate and differentiate BMSCs and deliver BMP-2 is a crucial technology in BMSC-based tissue engineering. METHODS: The proliferation of mouse BMSCs (mBMSCs) in collagen/poly-γ-glutamic acid (Col/γ-PGA) hydrogel was evaluated using LIVE/DEAD and acridine orange and propidium iodide assays. In vitro osteogenic differentiation and the gene expression level of Col/γ-PGA(mBMSC/BMP-2) were assessed by alizarin red S staining and quantitative reverse-transcription polymerase chain reaction. The bone regeneration effect of Col/γ-PGA(mBMSC/BMP-2) was evaluated in a mouse calvarial bone defect model. The cranial bones of the mice were monitored by micro-computed tomography and histological analysis. RESULTS: The developed Col/γ-PGA hydrogel showed low viscosity below ambient temperature, while it provided a high elastic modulus and viscous modulus at body temperature. After gelation, the Col/γ-PGA hydrogel showed a 3D and interconnected porous structure, which helped the effective proliferation of BMSCs with BMP-2. The Col/γ-PGA (mBMSC/BMP-2) expressed more osteogenic genes and showed effective orthotopic bone formation in a mouse model with a critical-sized bone defect in only 3–4 weeks. CONCLUSION: The Col/γ-PGA(mBMSC/BMP-2) hydrogel was suggested to be a promising platform by combining collagen as a major component of the extracellular matrix and γ-PGA as a viscosity reducer for easy handling at room temperature in BMSC-based bone tissue engineering scaffolds. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13770-022-00454-4.

Enterococcus faecalis, a Gram-positive opportunistic pathogen having lipoteichoic acid (LTA) as a major virulence factor, is closely associated with refractory apical periodontitis. Short-chain fatty acids (SCFAs) are found in the apical lesion and may affect inflammatory responses induced by E. faecalis. In the current study, we investigated inflammasome activation by E. faecalis LTA (Ef.LTA) and SCFAs in THP-1 cells. Among SCFAs, butyrate in combination with Ef.LTA markedly enhanced caspase-1 activation and IL-1β secretion whereas these were not induced by Ef.LTA or butyrate alone. Notably, LTAs from Streptococcus gordonii, Staphylococcus aureus, and Bacillus subtilis also showed these effects. Activation of TLR2/GPCR, K+ efflux, and NF-κB were necessary for the IL-1β secretion induced by Ef.LTA/butyrate. The inflammasome complex comprising NLRP3, ASC, and caspase-1 was activated by Ef.LTA/butyrate. In addition, caspase-4 inhibitor diminished IL-1β cleavage and release, indicating that non-canonical activation of the inflammasome is also involved. Ef.LTA/butyrate induced Gasdermin D cleavage, but not the release of the pyroptosis marker, lactate dehydrogenase. This indicated that Ef.LTA/butyrate induces IL-1β production without cell death. Trichostatin A, a histone deacetylase (HDAC) inhibitor, enhanced Ef.LTA/butyrate-induced IL-1β production, indicating that HDAC is engaged in the inflammasome activation. Furthermore, Ef.LTA and butyrate synergistically induced the pulp necrosis that accompanies IL-1β expression in the rat apical periodontitis model. Taken all these results together, Ef.LTA in the presence of butyrate is suggested to facilitate both canonical- and non-canonical inflammasome activation in macrophages via HDAC inhibition. This potentially contributes to dental inflammatory diseases such as apical periodontitis, particularly associated with Gram-positive bacterial infection.

Background The COVID-19 pandemic has disrupted malaria control activities globally. Notably, high levels of excess malaria morbidity and mortality in low- and middle-income countries (LMICs) were reported. Although it is crucial to systematically understand the main causes of the disruption to malaria control and synthesize strategies to prepare for future pandemics, such studies are scarce. Therefore, this study aims to better identify barriers against and strategies for malaria control. Methods Following the PRISMA guidelines and through searches of electronic databases and Google Scholar, a systematic literature review was conducted to identify studies pertaining to malaria control published between January 2020 and December 2021. Only studies that discussed reported barriers and/or strategies related to malaria were included for the review. The Mixed Methods Quality Appraisal Tool (MMAT) and the Authority, Accuracy, Coverage, Objectivity, Date and Significance (AACODS) checklist were used for quality appraisal. Key information such as literature type, study design, setting and population, interventions, outcomes, barriers, and strategies were extracted. With an existing framework of four dimensions (accessibility, affordability, availability, and acceptability) further subdivided by the supply and demand sides, this study synthesized information on barriers and strategies related to malaria control and further categorized the strategies based on the time frame. Results From the 30 selected studies, 27 barriers and 39 strategies were identified. The lockdown measures, which mainly threatened geographic accessibility and availability of malaria control services, were identified to be the main barrier hindering effective mobilization of community health workers and resources. Among the identified strategies, clear risk communication strategies would alleviate psychosocial barriers, which challenged acceptability. Some strategies that cross-cut points across all four dimensions would, require systems-level integration to enhance availability and affordability of malaria control. The strategies were distinguished between short-term, for instant response, and mid to long-term for future readiness. Conclusions The pandemic resulted in complex barriers to malaria control, particularly imposing a double burden on LMICs. Identifying strategies to overcome said barriers provides useful insights in the decision-making processes for the current and future pandemic. Cross-cutting strategies that integrate all dimensions need to be considered. Health system strengthening and resilience strategy appropriate for country-specific context is fundamental.

Let $NFA_b(q)$ denote the set of languages accepted by nondeterministic finite automata with $q$ states over an alphabet with $b$ letters. Let $B_n$ denote the set of words of length $n$. We give a quadratic lower bound on the VC dimension of \[ NFA_2(q)\cap B_n = \{L\cap B_n \mid L \in NFA_2(q)\} \] as a function of $q$. Next, the work of Gruber and Holzer (2007) gives an upper bound for the nondeterministic state complexity of finite languages contained in $B_n$, which we strengthen using our methods. Finally, we give some theoretical and experimental results on the dependence on $n$ of the VC dimension and testing dimension of $NFA_2(q)\cap B_n$., Comment: ISAIM 2020 (International Symposium on Artificial Intelligence and Mathematics), Fort Lauderdale, FL. January 6--8, 2020. Accepted for publication in Annals of Mathematics and Artificial Intelligence

The amino acid concentration of soybean products is important for nutritional and health benefits along with desirable sensory characteristics, but these properties could be affected by the origin of raw ingredients, processing method, and storage. Here, we aimed to evaluate the compositional characteristics of free amino acids in soybean paste and identify potential differences between those generated by traditional and nontraditional manufacturing processes. We developed and validated a high-performance liquid chromatography-diode array detection (HPLC-DAD) method involving sample derivatization to analyze 21 free amino acids in soybean pastes. All amino acid compounds were separated within 45 min using a C18 column (250 mm × 4.6 mm, 3 μm). Validation of the optimized 21 free amino acid analysis method showed good linearity (R2 > 0.993), accuracy (≥ 80%), intra- (≤10.63%) and inter-day (≤ 11.58%) repeatability, and limit of quantification (0.025–1.91 µg/g). The levels of 21 free amino acids in nontraditional and traditional soybean pastes detected based upon the optimized method were total amino acid detection levels at 55.3–150.9 (average 92.7) and 49.6–143.4 (average 86.8) mg/kg, respectively. Moreover, we confirmed that the composition ratios of glutamic acid, histidine, and sacrosine were higher in nontraditional soybean paste manufacturing methods (p

Personal dosimeters are used to measure the amount of radiation exposure in individual radiation workers. We aimed to replace existing personal dosimeters and evaluate a real-time scintillator-based dosimeter by monitoring its radiation dose and checking the location exposed to radiation in the workspace. The developed dosimeter measured the radiation dose based on a scintillating fiber (SF) bundle, and comprised a silicon photomultiplier (SiPM), ultra-wide-band (UWB)-based location detecting system, and Bluetooth system. The SF bundle was exposed to radiation-emitted light, and the photons were amplified and converted to electrical signals through the SiPM. These signals were transferred to the user through the Bluetooth system and monitored. To evaluate the feasibility of this mechanism as a dosimeter, we performed characteristic tests, such as dose linearity, dependence on dose rate, energy, exposed angle, and location coordinate mapping. Also, the dose distribution formed in circles around the iso-center was measured to confirm the feasibility of monitoring the exposure dose and location and to enable the radiation worker to move freely in a workspace. We confirmed dose linearity, independence from energy and angle, and accuracy of location monitoring in our device. The user’s locations were measured with a difference of − 6 cm and − 4.8 cm on the x- and the y-axes, respectively. The measured doses on our developed dosimeter were 62.7, 32.3, 21.0, and 15.4 mSv at distances of 50, 100, 150, and 200 cm from the iso-center. In other words, all measured doses at several points showed an error within 5% as compared to doses provided by the conventional pocket dosimeter. These results show that the developed SF-based dosimeter is advantageous in monitoring the exposure dose and location in real time, and has significant potential as a new personal dosimeter for radiation workers.

The global incidence of early-onset colorectal cancer (EO-CRC) is rapidly rising. However, the reason for this rise in incidence as well as the genomic characteristics of EO-CRC remain largely unknown. We performed whole-exome sequencing in 47 cases of EO-CRC and targeted deep sequencing in 833 cases of CRC. Mutational profiles of EO-CRC were compared with previously published large-scale studies. EO-CRC and The Cancer Genome Atlas (TCGA) data were further investigated according to copy number profiles and mutation timing. We classified colorectal cancer into three subgroups: the hypermutated group consisted of mutations in POLE and mismatch repair genes; the whole-genome doubling group had early functional loss of TP53 that led to whole-genome doubling and focal oncogene amplification; the genome-stable group had mutations in APC and KRAS, similar to conventional colon cancer. Among non-hypermutated samples, whole-genome doubling was more prevalent in early-onset than in late-onset disease (54% vs 38%, Fisher’s exact P = 0.04). More than half of non-hypermutated EO-CRC cases involved early TP53 mutation and whole-genome doubling, which led to notable differences in mutation frequencies between age groups. Alternative carcinogenesis involving genomic instability via loss of TP53 may be related to the rise in EO-CRC., Colorectal cancer: tumor genetic classification could help guide treatment Researchers in South Korea have identified distinct types of genetic changes in colorectal cancer (CRC). Groups led by Tae Won Kim at the University of Ulsan, Seoul, and Jong-il Kim at Seoul National University looked for mutations in genes in tumors from 880 patients, including all active genes in 47 patients with early-onset colorectal cancer (EO-CRC). The cancers were classified into three subgroups. A “hypermutated” group had mutations in genes involved in DNA replication and repair. The entire genome was doubled in another group, which included the EO-CRC cases. In this group, TP53 gene function, which is known to be crucial in suppressing tumor formation, was lost. A third group had mutations in two other identified genes. Identifying which subgroups patients belong to may help determine the best treatment option.

Background The aim of this study was to evaluate the influence of increased irradiation distance on the flexural strength (FS), dentin micro-shear bond strength (μSBS), and the degree of conversion (DC) of bulk-fill flowable, conventional flowable, and packable resin composites. Methods The resin composites tested were Surefil® SDR™ (SDR), Filtek Z350 XT Flowable Restorative A2 shade (Z3F), and Filtek Z350 XT Universal Restorative A2 shade (Z3P). Specimens were cured at four irradiation distances (0, 2, 4, and 8 mm) with an Elipar DeepCure-S LED curing light for 20 s. FS tests were performed (n = 15) using bar-shaped specimens (8 mm × 2 mm × 2 mm) of the resin composites. μSBS tests were performed on the occlusal surfaces of extracted third molars from humans that were ground to expose dentin (n = 15). DC was measured by using Raman spectroscopy on the top and bottom surfaces of disk specimens (2-mm thick) (n = 3). To further investigate whether extended irradiation times could compensate for reduced irradiance, additional Z3P specimens were prepared, which were light-cured at 8-mm distances for 40 and 60 s and subjected to FS tests, μSBS tests, and Raman spectroscopy. Both two-way and one-way ANOVA were used for statistical analyses. Results Both FS and DC of Z3P specimens cured at an 8-mm distance were significantly lower than those cured at shorter distances (p Conclusions Increasing the irradiation distance to 8 mm can have a deleterious influence on mechanical performances, including the FS, DC, and dentin μSBS, of the resin composites polymerized with high-irradiance light curing units.

Air pollution and smoking are associated with various types of mortality, including cancer. The current study utilizes a publicly accessible, nationally representative cohort to explore relationships between fine particulate matter (PM2.5) exposure, smoking, and cancer mortality. National Health Interview Survey and mortality follow-up data were combined to create a study population of 635,539 individuals surveyed from 1987 to 2014. A sub-cohort of 341,665 never-smokers from the full cohort was also created. Individuals were assigned modeled PM2.5 exposure based on average exposure from 1999 to 2015 at residential census tract. Cox Proportional Hazard models were utilized to estimate hazard ratios for cancer-specific mortality controlling for age, sex, race, smoking status, body mass, income, education, marital status, rural versus urban, region, and survey year. The risk of all cancer mortality was adversely associated with PM2.5 (per 10 µg/m3 increase) in the full cohort (hazard ratio [HR] 1.15, 95% confidence interval [CI] 1.08–1.22) and the never-smokers’ cohort (HR 1.19, 95% CI 1.06–1.33). PM2.5-morality associations were observed specifically for lung, stomach, colorectal, liver, breast, cervix, and bladder, as well as Hodgkin lymphoma, non-Hodgkin lymphoma, and leukemia. The PM2.5-morality association with lung cancer in never-smokers was statistically significant adjusting for multiple comparisons. Cigarette smoking was statistically associated with mortality for many cancer types. Exposure to PM2.5 air pollution contributes to lung cancer mortality and may be a risk factor for other cancer types. Cigarette smoking has a larger impact on cancer mortality than PM2.5 , but is associated with similar cancer types.

In this paper, the multiple frequency tracking and mitigation method based on the reassigned smoothed pseudo Wigner-Ville distribution (RSPWVD) and an adaptive multiple linear Kalman notch filter (AMLKNF) is proposed to track and mitigate multiple global positioning system (GPS) interference signals. Compared to the conventional notch filters, the AMLKNF has a faster convergence rate and smaller signal loss. However, for using this method, we need to know the notch frequency which is the interference frequency to remove. Thus, we use the RSPWVD method, one of the time-frequency analysis methods. In addition, an adaptation logic is designed in the AMLKNF to adjust the notch depth according to the power of the jamming signal. Matlab-based simulations are performed for analyzing the performance of the proposed method. The simulation results show that the proposed algorithm can efficiently track and eliminate interference well compared to the conventional methods.

Background The addition of bioactive glass (BG), a highly bioactive material with remineralization potential, might improve the drawback of weakening property of mineral trioxide aggregates (MTA) when it encounters with body fluid. This study aims to evaluate the effect of BG addition on physical properties of MTA. Methods ProRoot (MTA), and MTA with various concentrations of BG (1, 2, 5 and 10% BG/MTA) were prepared. Simulated body fluid (SBF) was used to investigate the effect of the storage solution on dentin remineralization. Prepared specimens were examined as following; the push-out bond strength to dentin, compressive strength, setting time solubility and X-ray diffraction (XRD) analysis. Results The 2% BG/MTA showed higher push-out bond strengths than control group after 7 days of SBF storage. The 2% BG/MTA exhibited the highest compressive strength. Setting times were reduced in the 1 and 2% BG/MTA groups, and solubility of all experimental groups were clinically acceptable. In all groups, precipitates were observed in dentinal tubules via SEM. XRD showed the increased hydroxyapatite peaks in the 2, 5 and 10% BG/MTA groups. Conclusion It was verified that the BG-added MTA increased dentin push-out bond strength and compressive strength under SBF storage. The addition of BG did not negatively affect the MTA maturation reaction; it increased the amount of hydroxyapatite during SBF maturation.

Tyrosine kinase inhibitor-induced hypothyroidism is associated with favorable survival in patients with various cancers. We aimed to investigate the incidence of regorafenib-induced hypothyroidism and assess its prognostic value in patients with metastatic or unresectable colorectal cancer (CRC) receiving regorafenib. This study included 68 patients treated at Asan Medical Center (Seoul, Republic of Korea) between 2014 and 2016 with metastatic or unresectable CRC refractory to standard therapies. Regorafenib (160 mg/day on days 1–21 followed by a 7-day break) was administered. The median patient age was 58 (range 26–72) years; 61.8% of patients were male. Among the 68 patients, 50 (73.5%) showed hypothyroidism; 39 (57.4%) had subclinical and 11 (16.2%) had symptomatic hypothyroidism. Overall, the objective response rate (ORR) and disease control rate (DCR) were 7.4% and 70.6%, respectively; both were significantly higher in patients with symptomatic or subclinical hypothyroidism than in euthyroid patients (ORR 27.3% vs. 5.1% vs. 0.0%, P = 0.001; DCR 100% vs. 76.9% vs. 38.9%, P = 0.001). Median progression-free survival (PFS) and overall survival (OS) were longer in patients with symptomatic hypothyroidism than in those with subclinical hypothyroidism (median PFS 9.1 vs. 3.8 months, P = 0.018; median OS: 19.2 vs. 9.4 months, P = 0.012) or with euthyroid status (median PFS 9.1 vs. 1.8 months, P

Oxidative stress caused by free radicals has been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS). Edaravone (also known as MCI-186), a free radical scavenger, was approved as an ALS treatment in 2015 in Japan. However, the therapeutic effects of edaravone on patients with ALS outside of Japan are not yet reported. This study aims to investigate effects of edaravone on ALS patients in the Korean population. The study included 22 patients with ALS who were treated with edaravone. Of the 16 patients who finished six cycles of treatment, a mean decline of ALSFRS-R after the treatments was 5.75 ± 6.07 points and the average change of FVC was - 8.7 ± 17.0%. Patients experienced only minor adverse events. This study reports on the open-label study of edaravone on patients in Korea for ALS patients, which showed a modest effect of edaravone in this population of ALS patients.

A multi-decade decline in the concentrations of fine particles (PM2.5) has benefited public health greatly by reducing the incidence of premature death and illnesses. A large body of literature has examined the change over time in this burden among the US population. However, less is known about these changes have affected subgroups most vulnerable and susceptible to poor air quality. In this study, we applied the results of an air quality prediction model that estimated changes in PM2.5 between 1980 and 2010 across all counties in the contiguous US. For the year 1980, we defined groups of vulnerable and susceptible populations according to attributes including county-level educational attainment, income, urbanicity, and all-cause death rate. Using a health impact function, we quantified PM2.5-attributable premature deaths for 1980 and 2010 among the overall US population as well as these subgroups. We then used the Atkinson index to explore the inequality in the absolute level and change in PM2.5 mortality among and between these subgroups. Between 1980 and 2010, total PM2.5 mortality risk declined for all groups. Risk inequality fell across all population groups and the risk experienced among each vulnerable and susceptible group became more equitably distributed. These results suggest that falling ambient PM2.5 concentrations over a 30-year period yield significant benefits among populations most susceptible and vulnerable to poor air quality. Furthermore, our results imply that policies including the Clean Air Act were effective at reducing health disparities.

Perception has recently been highlighted as a critical determinant for participation in clinical trials (CTs) among cancer patients. We evaluated cancer patients’ current perceptions of CTs using the PARTAKE questionnaires, focusing on differences between patients with common and rare cancers. From November 2015 to May 2017, we prospectively surveyed patients who had received anti-cancer treatment at Asan Medical Center. Among 333 respondents, 70.9% had common and 29.1% had rare cancers. In the cohort, 87.7% of patients with common cancers and 75.3% of patients with rare cancers answered that they heard of and knew about CTs. However, willingness to participate in CTs was expressed only in approximately 56% of patients, although it was significantly associated with awareness and perception. Surprisingly, patients with rare cancers when compared with patients with common cancers showed significantly lower levels of awareness and perception (64.2% vs 79.9%, p = 0.003 and 77.3% vs 91.9%, p

This mixed methods study explored how Saudi Arabia’s science education reform is functioning in 2 public girls’ secondary schools located in Dammam, 1 of the main cities in Saudi Arabia. Saudi Arabia recently launched a new initiative to promote science education innovation by providing science curriculum change, professional development for science teachers, and progress towards a new educational system. This study examined Saudi secondary girls’ perceptions regarding science learning environments and the metacognitive science learning orientation within the context of science education reform in Saudi Arabia (N = 202). Further, 3 science teacher participants were interviewed in order to ascertain their perceptions of their current science teaching environments and their science teaching. Particular emphasis was placed on examining differences between the Course System, which is a new system designed to facilitate science experiments and constructivist teaching and learning, and the regular system in terms of students’ perceptions about science learning environments and their metacognitive science learning orientation. Results and findings indicate that teachers supported the constructivist pedagogy, and science education reform efforts may gradually change Saudi science education environments and improve Saudi girls’ science metacognitive learning orientation.

Background While many studies reported the association between long-term exposure to particulate matter air pollution (PM) and cardiovascular disease (CVD), few studies focused on incidence with relatively high-dose exposure using a nationwide cohort. This study aimed to investigate the association between long-term exposure to PM10 and PM2.5 and incidence of CVD in a nationwide and population-based cohort in South Korea where the annual average concentration of PM2.5 is above 20 μg/m3. Methods We selected 196,167 adults in the National Health Insurance Service-National Sample Cohort (NHIS-NSC) constructed based on the entire South Korean population. Incidence of four CVD subtypes including ischemic heart disease (IHD), myocardial infarction, heart failure, and stroke, and total CVD including all four was identified as the first diagnosis for 2007–2015. To assess individual exposures, we used annually-updated district-level residential addresses and district-specific PM concentrations predicted by a previously developed universal kriging prediction model. We computed individual-level long-term PM concentrations for four exposure windows: previous 1, 3, and 5 year(s) and 5 years before baseline. We applied time-dependent Cox proportional hazards models to estimate hazard ratios (HRs) of incident CVDs per 10 μg/m3 increase in PM10 and PM2.5 after adjusting for individual- and area-level characteristics. Results During 1,578,846 person-year, there were 33,580 cases of total incident CVD. Average PM10 and PM2.5 concentrations for the previous 5 years were 52.3 and 28.1 μg/m3, respectively. A 10 μg/m3 increase in PM2.5 exposed for the previous 5 years was associated with 4 and 10% increases in the incidence of total CVD (95% confidence interval: 0–9%) and IHD (4–16%), respectively. HRs tended to be higher with earlier exposure for IHD and more recent exposure for stroke. The estimated shape of the concentration-response relationship showed non-linear patterns. We did not find evidence of the association for PM10. Conclusions Using a population-based nationwide cohort exposed to relatively high PM concentration, this study confirmed the association between PM2.5 and CVD incidence that was reported in previous studies mostly with low-dose environments. The magnitude and the shape of the association were generally consistent with previous findings.

Background We evaluated the toxicity of 5% (w/v) povidone-iodine (PI) applied to the ocular surface of rabbits. Methods Twenty-three white rabbits were divided into four groups; these were a control group and three study groups in which the ocular surface was exposed to PI for different times. In control group, one drop of phosphate-buffered saline (PBS) was applied once for 10 min. In study groups, one drop of 5% (w/v) PI was topically applied once for 1 min, 3 min, and 10 min, and then the animals were observed for 7 days. The Schirmer test, Rose Bengal staining, corneal fluorescein staining and conjunctival impression cytology were performed on day 0, 3, and 7. After 7 days, the rabbits were sacrificed and conjunctiva and cornea were collected and evaluated by light and electron microscope. Immunofluorescence staining was also performed to detect mucin 5 subtype AC (MUC5AC). Results The decrease in goblet cell density, reductions in MUC5AC level and histopathological and ultrastructural changes of conjunctiva and cornea were more prominent in the 5% (w/v) PI groups than the control group (p p values Conclusions 5% (w/v) povidone-iodine caused damages to the ocular surface in a time-dependent manner. Therefore, we should be aware of that excessive PI exposure during ophthalmic procedures could be a pathogenic factor of dry eye syndrome after surgery.

Although carbohydrate antigen 19-9 (CA 19-9) may be elevated in benign diseases, elevated CA 19-9 may cause a fear of cancer and unnecessary follow-up studies. Research on how to approach systematically in this case is very limited. The purpose of this study was to analyze the clinical features and the causes of CA 19-9 elevation without evidence of malignant or pancreatobiliary diseases. We retrospectively reviewed the medical records of patients who had CA 19-9 elevation (≥80 U/mL) and were found to be unrelated to cancer after follow-up. After exclusion, 192 patients were included in this study. The median level of CA 19-9 was 136.5 U/mL. The causes of CA 19-9 elevation were determined in 147 (76.6%) patients, and that was unknown in 45 (23.4%). The estimated causative diseases were hepatic diseases in 63 patients, pulmonary diseases in 32, gynecologic diseases in 38, endocrine diseases in 13, and spleen disease in 1. Of 45 patients with unknown cause, 35 had normalization of CA 19-9 and 10 had persistently elevated CA 19-9. In conclusion, CA 19-9 elevation without malignancies or pancreatobiliary diseases should be systematically evaluated and followed up. We suggest an algorithm to investigate the causes and follow up these patients.

Lanreotide autogel is a long-acting somatostatin analogue with proven efficacy and safety in patients with well-differentiated (WD) gastroenteropancreatic-neuroendocrine tumors (GEP-NETs) in a prior randomized phase III trial (CLARINET). However, the CLARINET study only enrolled patients with Ki-67 index10%, and few patients of Asian ethnicity were included. We retrospectively analyzed the efficacy and safety of lanreotide in Korean patients with GEP-NETs in the daily practice setting. Between January 2015 and May 2018, 64 patients with metastatic WD GEP-NETs received lanreotide at Asan Medical Center, Seoul, Korea. Of them, 45 (70.3%) patients who received lanreotide as monotherapy were included in the current analysis. The most common primary tumor site was the pancreas (n = 22, 48.9%), followed by the rectum (10, 22.2%) and the small bowel (7, 15.6%). According to RECIST v1.1, a partial response was achieved in one patient (2.2%) and stable disease was achieved in 40 patients (88.9%). The median progression-free survival (PFS) was 16.4 months (95% confidence interval, 9.5-23.3 months). There were no differences in PFS according to the primary tumor site (p = 0.77). Hepatic tumor volume 25% and prior systemic therapy were significantly associated with poorer PFS in the multivariate analysis. Lanreotide is well-tolerated and effective for Korean patients with GEP-NETs in the daily practice setting.

We recently demonstrated the biosynthesis of 24-ethylidene brassinosteroids in Arabidopsis thaliana. To determine the physiological role of biosynthesis of 24-ethylidene brassinosteroids, metabolism of 28-homodolichosterone as the end product of 24-ethylidene brassinosteroids biosynthesis was examined by a crude enzyme solution prepared from A. thaliana. In wild-type plants, dolichosterone and castasterone were identified as enzyme products on GC-MS analysis. In a mutant where DWARF1 was overexpressed (35S-DWF1), the conversion rate of 28-homodolichosterone to castasterone was significantly increased. These results indicate that conversion of 28-homodolichosterone to castasterone is mediated by dolichosterone in Arabidopsis. In the root growth assay, inhibitory activity was enhanced in the order of castasterone > dolichosterone > 28-homodolichosterone, demonstrating that conversion of 28-homodolichosterone to castasterone via dolichosterone is a biosynthetic reaction that increases BR activity in Arabidopsis. Compared to Arabidopsis grown under dark conditions, light-grown Arabidopsis showed up-regulated DWARF1 expression, resulting in an increased conversion rate of 28-homodolichosterone to castasterone, suggesting that light is an important regulatory factor for the biosynthetic connection of 24-ethylidene brassinosteroids and 24-methyl brassinosteroids in A. thaliana. Consequently, 24-ethylidene brassinosteroids biosynthesis to generate 28-homodolichosterone is a lightregulated alternative route for synthesis of the biologically-active BRs, castasterone and brassinolide in Arabidopsis plants.

The tumor suppressor gene CD82/KAI1 is a member of the tetraspanin superfamily and organizes various membrane-based processes. Mycobacterium tuberculosis (MTB) persists in host macrophages by interfering with phagolysosome biogenesis and inflammatory responses, but the role of CD82 in controlling the intracellular survival of pathogenic mycobacteria within macrophages remains poorly understood. In this study, we demonstrated that the virulent MTB strain H37Rv (MTB Rv) induced CD82 promoter hypomethylation, resulting in CD82 expression. Targeting of the runt-related transcription factor 1 (RUNX1) by CD82 is essential for phagosome arrest via interacting with Rab5/22. This arrest is required for the intracellular growth of MTB in vitro and in vivo, but not for that of MTB H37Ra (MTB Ra) in macrophages. In addition, knockdown or knockout of CD82 or RUNX1 increased antibacterial host defense via phagolysosome biogenesis, inflammatory cytokine production, and subsequent antimicrobial activity both in vitro and in vivo. Notably, the levels of CD82 and RUNX1 in granulomas were elevated in tuberculosis (TB) patients, indicating that CD82 and RUNX1 have clinical significance in human TB. Our findings identify a previously unrecognized role of CD82 hypomethylation in the regulation of phagosome maturation, enhanced intracellular survival, and the innate host immune response to MTB. Thus, the CD82–RUNX1–Rab5/22 axis may be a previously unrecognized virulence mechanism of MTB pathogenesis., Tuberculosis: Evading host defences The tuberculosis-causing bacterium Mycobacterium tuberculosis regulates a tumor suppressor gene in order to survive and grow in host immune cells. Chul-Su Yang and colleagues at Hanyang University, South Korea, have found that the bacterium can stimulate the expression of CD82 in macrophages by removing methyl groups from its DNA sequence. CD82’s hypomethylated region interacts with and activates proteins that interfere with the cell’s ability to mount an inflammatory response and degrade bacteria in specialized intracellular vesicles called lysosomes. The increased survival rate of CD82-deficient mice following infection with tuberculosis and the elevated levels of CD82 protein found in the inflammatory lesions of patients with tuberculosis further support a previously unrecognized role for this protein in M. tuberculosis infection. Targeting CD82-mediated signaling could be a promising approach for designing new therapeutics.

Background Older patients have increased risk of toxicity from chemotherapy. Current prediction tools do not provide information on cumulative risk. Methods Patients aged ≥ 70 years with solid cancer were prospectively enrolled. A prediction model was developed for adverse events (AEs) ≥ Grade 3 (G3), based on geriatric assessment (GA), laboratory, and clinical variables. Results 301 patients were enrolled (median age, 75 years). Median number of chemotherapy cycles was 4. During first-line chemotherapy, 53.8% of patients experienced AEs ≥ G3. Serum protein < 6.7 g/dL, initial full-dose chemotherapy, psychological stress or acute disease in the past 3 months, water consumption < 3 cups/day, unable to obey a simple command, and self-perception of poor health were significantly related with AEs ≥ G3. A predicting model with these six variables ranging 0–8 points was selected with the highest discriminatory ability (c-statistic= 0.646), which could classify patients into four risk groups. Predicted cumulative incidence of AEs ≥ G3 was discriminated according to risk groups. Conclusions This prediction tool could identify the risk of AEs ≥ G3 after chemotherapy and provide information on the cumulative incidence of AEs in each cycle. Clinical Trial Id WHO ICTRP number, KCT0001071

Isofucosterol is a major 4-demethylsterol which has an ethylidene group at C-24 in Arabidopsis thaliana. To evaluate the presence of brassinosteroids (BRs) with the same carbon skeleton as that of isofucosterol, a large quantity of A. thaliana was extracted and purified. GC-MS/selected ion monitoring analysis verified that 6-deoxohomodolichosterone and homodolichosterone are present in Arabidopsis. An enzyme solution prepared from wild type Arabidopsis successfully mediated conversion of 6-deoxohomodolichosterone to homodolichosterone. However, a double mutant cyp85a1/cyp85a2 could not catalyze the conversion, implying that in A. thaliana the C-6 oxidation of 6-deoxohomodolichosterone to homodolichosterone seems to be catalyzed by CYP85A1 and/or CYP85A2. In yeast, both heterologously expressed CYP85A1 and CYP85A2 catalyzed the C-6 oxidation of 6- deoxohomodolichosterone to homodolichosterone, but the conversion rate in CYP85A2/V60/WAT21 was significantly higher than that in CYP85A1/V60/WAT21, indicating that C-6 oxidation of 6-deoxohomodolichosterone to homodolichosterone is mainly catalyzed by CYP85A2 in A. thaliana. Taken together, this study strongly suggests that a biosynthetic pathway for the production of 6-deoxohomodolichosterone and homodolichosterone is functional, and CYP85As have important roles in 24-ethylidene biosynthesis in A. thaliana.

Some clinicopathological variables are known to influence the survival of patients with advanced gastric cancer. A comprehensive model based on these factors is needed for prediction of an individual’s survival and appropriate patient counseling. A nomogram for predicting 1-year survival in patients with advanced gastric cancer in the palliative chemotherapy setting was developed using clinicopathological data from 949 patients with unresectable or metastatic gastric cancer who had received first-line doublet cytotoxic chemotherapy from 2001 to 2006 at the National Cancer Center, Korea (Baseline Nomogram). For 836 patients whose initial response to chemotherapy is known, another nomogram (ChemoResponse-based Nomogram) was constructed using the response to chemotherapy as additional variable. Nomogram performance in terms of discrimination and calibration ability was evaluated using the C statistic and Hosmer–Lemeshow-type χ 2 statistics. Two different nomograms were developed and subjected to internal validation. The baseline nomogram incorporated 13 baseline clinicopathological variables, whereas the chemoresponse-based nomogram was composed of 11 variables including initial response to chemotherapy. Internal validation revealed good performance of the two nomograms in discrimination: C statistics = 0.656 (95% confidence interval, 0.628–0.673) for the baseline and 0.718 (95% confidence interval, 0.694–0.741) for the chemoresponse-based nomogram, which showed significantly better discrimination performance than the baseline nomogram (Z statistics = 3.74, p

Conjugated polymer nanoparticles were successfully capped with a commercially available triblock copolymer Pluronic F127® to form stable nanoparticles with the potential for photodynamic therapy (PDT) of cancer cells. PDT is known as an effective, simple treatment method without the need for surgery. Investigations on the particle structure revealed that the nanoparticles were fabricated with a core-shell structure of ~192 nm. The PDT effects of the nanoparticles on HeLa cancer cells were investigated via cell imaging and cytotoxicity tests. The nanoparticles were biocompatible and were easily internalized by HeLa cells. Moreover, the nanoparticles efficiently generated reactive oxygen species to kill cancer cells under UV irradiation. Therefore, the nanoparticles have promising applications for cancer cell imaging and therapy.

Hepatocyte growth factor (HGF) and its receptor, cMet, activate biological pathways necessary for repair and regeneration following kidney injury. Because HGF is a highly unstable molecule in its biologically active form, we asked whether a monoclonal antibody (Ab) that displays full agonist activity at the receptor could protect the kidney from fibrosis. We attempted to determine whether the cMet agonistic Ab might reduce fibrosis, the final common pathway for chronic kidney diseases (CKD). A mouse model of kidney fibrosis disease induced by unilateral ureteral obstruction was introduced and subsequently validated with primary cultured human proximal tubular epithelial cells (PTECs). In kidney biopsy specimens from patients with CKD, cMet immunohistochemistry staining showed a remarkable increase compared with patients with normal renal functions. cMet Ab treatment significantly increased the levels of phospho-cMet and abrogated the protein expression of fibrosis markers such as fibronectin, collagen 1, and αSMA as well as Bax2, which is a marker of apoptosis triggered by recombinant TGF-β1 in PTECs. Remarkably, injections of cMet Ab significantly prevented kidney fibrosis in obstructed kidneys as quantified by Masson trichrome staining. Consistent with these data, cMet Ab treatment decreased the expression of fibrosis markers, such as collagen1 and αSMA, whereas the expression of E-cadherin, which is a cell-cell adhesion molecule, was restored. In conclusion, cMet-mediated signaling may play a considerable role in kidney fibrosis. Additionally, the cMet agonistic Ab may be a valuable substitute for HGF because it is more easily available in a biologically active, stable, and purified form.

Background Fetal growth has been known to be associated with particulate matter (PM) air pollution during gestation. Given that regular working may deviate outdoor air pollution exposure, the association between air pollution and fetal growth restriction can be different across maternal working status. This study was to assess possible effect modification by maternal employment in the association between exposure to PM during pregnancy and fetal growth restriction. Methods Using hourly PM less than or equal to 10 and 2.5 μm in diameter (PM10 and PM2.5) regulatory monitoring data for 2001–2012 and 2008–2012, respectively, and birth certificate data for 2002–2012, we computed maternal exposures with district-level averages of PM10 and PM2.5 during one year before birth, entire pregnancy, and the 1st, 2nd and 3rd trimesters. The outcomes of fetal growth restriction were assessed by small for gestational age (SGA, weighted

The impact of microsatellite instability (MSI) on survival in stage III colon cancer treated with adjuvant 5-fluorouracil–oxaliplatin combination (FOLFOX) chemotherapy is not clear. We evaluated the association between MSI and survival in this population. We analyzed 598 patients with curatively resected stage III colon cancer treated with adjuvant FOLFOX chemotherapy. We determined MSI status using polymerase chain reaction amplification; tumors were classified as high MSI (MSI-H, ≥2 unstable markers), low MSI (MSI-L, 1 unstable marker), or microsatellite stable (MSS, no unstable marker). Of 598 patients, 8.4% showed MSI-H. Tumors classified as MSI-H were more commonly located in the ascending colon (54.0 vs. 27.7%, p

Background: We assessed the treatment effect of panitumumab plus best supportive care (BSC) vs BSC on overall survival (OS) in patients with chemorefractory wild-type KRAS exon 2 metastatic colorectal cancer (mCRC) and report the first prospective extended RAS analysis in a phase 3 trial. Methods: Patients with wild-type KRAS exon 2 mCRC were randomised 1 : 1 to panitumumab (6 mg kg−1 Q2W) plus BSC or BSC. On-study crossover was prohibited. RAS mutation status was determined by central laboratory testing. The primary endpoint was OS in wild-type KRAS exon 2 mCRC; OS in wild-type RAS mCRC (KRAS and NRAS exons 2, 3, and 4) was a secondary endpoint. Results: Three hundred seventy seven patients with wild-type KRAS exon 2 mCRC were randomised. Median OS was 10.0 months with panitumumab plus BSC vs 7.4 months with BSC (HR=0.73; 95% CI=0.57–0.93; P=0.0096). RAS ascertainment was 86%. In wild-type RAS mCRC, median OS for panitumumab plus BSC was 10.0 vs 6.9 months for BSC (HR=0.70; 95% CI=0.53–0.93; P=0.0135). Patients with RAS mutations did not benefit from panitumumab (OS HR=0.99; 95% CI=0.49–2.00). No new safety signals were observed. Conclusions: Panitumumab significantly improved OS in wild-type KRAS exon 2 mCRC. The effect was more pronounced in wild-type RAS mCRC, validating previous retrospective analyses.

Although cohort studies of the health effects of PM2.5 have developed exposure prediction models to represent spatial variability across participant residences, few models exist for PM2.5 components. We aimed to develop a city-specific spatio-temporal prediction approach to estimate long-term average concentrations of four PM2.5 components including sulfur, silicon, and elemental and organic carbon for the Multi-Ethnic Study of Atherosclerosis cohort, and to compare predictions to those from a national spatial model. Using 2-week average measurements from a cohort-focused monitoring campaign, the spatio-temporal model employed selected geographic covariates in a universal kriging framework with the data-driven temporal trend. Relying on long-term means of daily measurements from regulatory monitoring networks, the national spatial model employed dimension-reduced predictors using universal kriging. For the spatio-temporal model, the cross-validated and temporally-adjusted R(2) was relatively higher for EC and OC, and in the Los Angeles and Baltimore areas. The cross-validated R(2)s for both models across the six areas were reasonably high for all components except silicon. Predicted long-term concentrations at participant homes from the two models were generally highly correlated across cities but poorly correlated within cities. The spatio-temporal model may be preferred for city-specific health analyses, whereas both models could be used for multi-city studies.

The effectiveness of regulatory actions designed to improve air quality is often assessed by predicting changes in public health resulting from their implementation. Risk of premature mortality from long-term exposure to ambient air pollution is the single most important contributor to such assessments and is estimated from observational studies generally assuming a log-linear, no-threshold association between ambient concentrations and death. There has been only limited assessment of this assumption in part because of a lack of methods to estimate the shape of the exposure-response function in very large study populations. In this paper, we propose a new class of variable coefficient risk functions capable of capturing a variety of potentially non-linear associations which are suitable for health impact assessment. We construct the class by defining transformations of concentration as the product of either a linear or log-linear function of concentration multiplied by a logistic weighting function. These risk functions can be estimated using hazard regression survival models with currently available computer software and can accommodate large population-based cohorts which are increasingly being used for this purpose. We illustrate our modeling approach with two large cohort studies of long-term concentrations of ambient air pollution and mortality: the American Cancer Society Cancer Prevention Study II (CPS II) cohort and the Canadian Census Health and Environment Cohort (CanCHEC). We then estimate the number of deaths attributable to changes in fine particulate matter concentrations over the 2000 to 2010 time period in both Canada and the USA using both linear and non-linear hazard function models. Electronic supplementary material The online version of this article (doi:10.1007/s11869-016-0398-z) contains supplementary material, which is available to authorized users.

The chloroplast is an essential organelle in microalgae for conducting photosynthesis, thus enabling the photoautotrophic growth of microalgae. In addition to photosynthesis, the chloroplast is capable of various biochemical processes for the synthesis of proteins, lipids, carbohydrates, and terpenoids. Due to these attractive characteristics, there has been increasing interest in the biotechnological utilization of microalgal chloroplast as a sustainable alternative to the conventional production platforms used in industrial biotechnology. Since the first demonstration of microalgal chloroplast transformation, significant development has occurred over recent decades in the manipulation of microalgal chloroplasts through genetic engineering. In the present review, we describe the advantages of the microalgal chloroplast as a production platform for various bioproducts, including recombinant proteins and high-value metabolites, features of chloroplast genetic systems, and the development of transformation methods, which represent important factors for gene expression in the chloroplast. Furthermore, we address the expression of various recombinant proteins in the microalgal chloroplast through genetic engineering, including reporters, biopharmaceutical proteins, and industrial enzymes. Finally, we present many efforts and achievements in the production of high-value metabolites in the microalgal chloroplast through metabolic engineering. Based on these efforts and advances, the microalgal chloroplast represents an economically viable and sustainable platform for biotechnological applications in the near future.

Background Previous studies suggested associations between prenatal exposure to air pollution and hypertensive disorders of pregnancy. We explored the associations between ambient concentrations of five major air pollutants during preconceptional and prenatal periods and three hypertensive disorders of pregnancy in Seoul, Korea, using a population-representative cohort. Methods We obtained heath and demographic data of pregnant women residing in Seoul for 2002–2013 from the Korean National Health Insurance Service–National Sample Cohort. For mother’s individual exposures to air pollution, we computed concentrations of particulate matter ≤10 μm in diameter (PM10), nitrogen dioxide (NO2), carbon monoxide (CO), sulfur dioxide (SO2), and ozone (O3) during 1, 3, 6, and 12 months to birth using regulatory monitoring data in Seoul. The associations between air pollution and hypertensive disorders were explored by using logistic regression models after adjusting for individual confounders. Results Among 18,835 pregnant women in Seoul, 0.6, 0.5, and 0.4% of women developed gestational hypertension, preeclampsia, and preeclampsia requiring magnesium sulfate (Mg-preeclampsia), respectively. Although most odds ratios (ORs) were not statistically significant, we found increasing risk gradients with disease severity depending on the pollutant. There was the association between PM10 during 6 months to birth and gestational hypertension (OR for an interquartile range increase = 1.68 [95% confidence interval = 1.09–2.58]). NO2 and ozone during 12 and 1 month, respectively, before birth were associated with Mg-preeclampsia (1.43 [1.01–2.03], 1.53 [1.03–2.27]). Conclusions We observed positive associations of exposure to some air pollutants before and during pregnancy with hypertensive disorders of pregnancy among the Korean general population. Future studies with refined exposure metrics should confirm our findings. Electronic supplementary material The online version of this article (10.1186/s12884-018-1982-z) contains supplementary material, which is available to authorized users.

Because the number of cytotoxic agents available for the treatment of metastatic colorectal cancer (mCRC) is limited, rechallenge with the same chemotherapy agents can provide a continuum of treatment. This study investigated the efficacy and feasibility of oxaliplatin rechallenge in mCRC patients who had been previously exposed to oxaliplatin-based chemotherapy. Patients were included if they had mCRC and evaluable disease, had remained disease-free or progression-free for at least 6 months after the last dose of prior oxaliplatin-based therapy, and were retreated with oxaliplatin therapy. Between January 2009 and May 2014, 110 patients were retreated with oxaliplatin-based regimens; of these, 42 (38.2%) had received prior oxaliplatin as adjuvant chemotherapy and 68 (61.8%) as palliative chemotherapy. The overall response rate to oxaliplatin rechallenge was 30.9% (34/110), and the disease control rate was 68.2% (75/110), with one patient achieving complete response, 33 achieving partial response, and 41 having stable disease. Median progression-free survival and overall survival following oxaliplatin rechallenge were 5.9 months (95% confidence interval [CI], 4.4-7.4 months) and 18.5 months (95% CI, 14.0-23.0 months), respectively. Sixteen patients experienced grade 2 or 3 neuropathy. Ten patients experienced any grade hypersensitivity reaction within four cycles of treatment, including six who stopped treatment due to grade 3 or 4 hypersensitivity reactions. Rechallenge with oxaliplatin-based therapy may be an option for patients who achieve at least 6 months of disease-free or progression-free survival with prior oxaliplatin-based chemotherapy. However, neurotoxicity and hypersensitivity reactions should be carefully monitored in this setting.

Calcium phosphate cements (CPCs) are synthetic bioactive cements widely used as hard tissue substitutes. Critical limitations of use include their poor mechanical properties and poor anti-washout behaviour. To address those limitations, we combined CPC with genetically engineered elastin-like polypeptides (ELPs). We investigated the effect of the ELPs on the physical properties and biocompatibility of CPC by testing ELP/CPC composites with various liquid/powder ratios. Our results show that the addition of ELPs improved the mechanical properties of the CPC, including the microhardness, compressive strength, and washout resistance. The biocompatibility of ELP/CPC composites was also comparable to that of the CPC alone. However, supplementing CPC with ELPs functionalized with octaglutamate as a hydroxyapatite binding peptide increased the setting time of the cement. With further design and modification of our biomolecules and composites, our research will lead to products with diverse applications in biology and medicine.

The aim of this study was to investigate the optimal conditions to process vitamin D2-fortified shiitake mushrooms through UV irradiation for industrial processing. Response surface methodology was used to identify the optimum conditions of the following highly influential factors on vitamin D2 synthesis: temperature, UV dosage, and moisture content. The optimal conditions of those variables were 40.56 °C, 36.27 kJ/m2, and 80.46%, respectively, and UV dosage was the most effective variable. The amount of vitamin D2 obtained under the optimal conditions was 29.87 ± 1.38 μg/g (dry mass: DM) which was well matched with the predicted value of 32.33 μg/g DM. The effects on the texture and color of shiitake mushrooms were also evaluated after the fortification process under the optimal conditions, and no adverse effects were observed compared to those of fresh shiitake mushrooms.

Background In metastatic colorectal cancer, the location of the primary tumor has been suggested to have biological significance. In this study, we investigated whether primary tumor location affects cetuximab efficacy in patients with RAS wild-type metastatic colorectal cancer. Methods Genotyping by the SequenomMassARRAY technology platform (OncoMap) targeting KRAS, NRAS, PIK3CA, and BRAF was performed in tumors from 307 patients who had been given cetuximab as salvage treatment. Tumors with mutated RAS (KRAS or NRAS; n = 127) and those with multiple primary location (n = 10) were excluded. Right colon cancer was defined as a tumor located in the proximal part to splenic flexure. Results A total of 170 patients were included in the study (right versus left, 23 and 147, respectively). Patients with right colon cancer showed more mutated BRAF (39.1% vs. 5.4%), mutated PIK3CA (13% vs. 1.4%), poorly differentiated tumor (17.4% vs. 3.4%), and peritoneal involvement (26.1% vs. 8.8%) than those with left colon and rectal cancer. Right colon cancer showed poorer progression-free survival (2.0 vs.5.0 months, P = 0.002) and overall survival (4.1 months and 13.0 months, P

Background Inflammatory bowel diseases (IBDs) are chronic inflammatory disorders that are mediated by pathogenic Th1 and Th17 cells. Previous studies have demonstrated that taheebo water extract (TWE) derived from Tabebuia avellanedae Lorentz ex Griseb., as folk remedy, has been used to treat various inflammatory diseases. Although TWE has been previously shown to display anti-inflammatory activities, the in vivo effects of TWE on mucosal immune responses remain unclear. Methods We examined the anti-inflammatory effects of TWE on innate immune cells such as dendritic cells (DCs) and macrophages and also on the differentiation of T helper cells. Lastly, adopting a method for dextran sulfate sodium (DSS)-induced colitis, we investigated whether the oral administration of TWE can modulate mucosal inflammatory responses. Results We found that TWE could activate DCs to produce immunosuppressive IL10 and polarize macrophages toward an anti-inflammatory phenotype in the mesenteric lymph node (MLN). Such alterations in DCs and macrophages resulted in a significant increase in anti-inflammatory Th2 and Foxp3+ Treg cells and a dramatic decrease in pro-inflammatory Th1 and Th17 cells in the MLN. Upon induction of colitis with DSS treatment, TWE significantly reduced the clinical symptoms, including body weight loss and colonic tissue inflammation, by up-regulating type II T helper immune responses. Conclusions Taken together, these data suggest that TWE is an excellent natural product with therapeutic effects to help improve inflammatory disorders such as colitis.

Background Mobile health (mHealth), a term used for healthcare delivery via mobile devices, has gained attention as an innovative technology for better access to healthcare and support for performance of health workers in the global health context. Despite large expansion of mHealth across sub-Saharan Africa, regional collaboration for scale-up has not made progress since last decade. Methods As a groundwork for strategic planning for regional collaboration, the study attempted to identify spatial patterns of mHealth implementation in sub-Saharan Africa using an exploratory spatial data analysis. In order to obtain comprehensive data on the total number of mHelath programs implemented between 2006 and 2016 in each of the 48 sub-Saharan Africa countries, we performed a systematic data collection from various sources, including: the WHO eHealth Database, the World Bank Projects & Operations Database, and the USAID mHealth Database. Additional spatial analysis was performed for mobile cellular subscriptions per 100 people to suggest strategic regional collaboration for improving mobile penetration rates along with the mHealth initiative. Global Moran’s I and Local Indicator of Spatial Association (LISA) were calculated for mHealth programs and mobile subscriptions per 100 population to investigate spatial autocorrelation, which indicates the presence of local clustering and spatial disparities. Results From our systematic data collection, the total number of mHealth programs implemented in sub-Saharan Africa between 2006 and 2016 was 487 (same programs implemented in multiple countries were counted separately). Of these, the eastern region with 17 countries and the western region with 16 countries had 287 and 145 mHealth programs, respectively. Despite low levels of global autocorrelation, LISA enabled us to detect meaningful local clusters. Overall, the eastern part of sub-Saharan Africa shows high-high association for mHealth programs. As for mobile subscription rates per 100 population, the northern area shows extensive low-low association. Conclusions This study aimed to shed some light on the potential for strategic regional collaboration for scale-up of mHealth and mobile penetration. Firstly, countries in the eastern area with much experience can take the lead role in pursuing regional collaboration for mHealth programs in sub-Saharan Africa. Secondly, collective effort in improving mobile penetration rates for the northern area is recommended. Electronic supplementary material The online version of this article (doi:10.1186/s12992-017-0286-9) contains supplementary material, which is available to authorized users.

This study aimed to evaluate the efficacy of a high dose of oral tegafur-uracil (400 mg/m2) plus leucovorin with preoperative chemoradiation of locally advanced rectal cancer and to explore the impact of polymorphisms of cytochrome P 2A6 (CYP2A6), uridine monophosphate synthetase (UMPS), and ATP-binding cassette B1 (ABCB1) on clinical outcome. Patients with cT3 or cT4 rectal cancer were enrolled and were given tegafur-uracil 400 mg/m2/day and leucovorin 90 mg/m2/day for 7 days a week during preoperative chemoradiation (50.4 Gy/28 fractions) in this phase II trial. Primary endpoint was pathologic complete response rate, and the secondary endpoint was to explore the association between clinical outcomes and genetic polymorphisms CYP2A6 (*4, *7, *9 and *10), UMPS G638C, and three ABCB1 genotypes (C1236T, C3435T, and G2677T). Ninety-one patients were given study treatment, and 90 underwent surgery. Pathologic complete response was noted in 10 patients (11.1%). There was no grade 4 or 5 toxicity; 20 (22.0%) experienced grade 3 toxicities, including diarrhea (10, 11.0%), abdominal pain (2, 2.2%), and anemia (2, 2.2%). Relapse-free survival and overall survival at 5 years were 88.6% and 94.2%, respectively. Patients with the UMPS 638 CC genotype experienced significantly more frequent grade 2 or 3 diarrhea (p for trend = 0.018). Preoperative chemoradiation with tegafur-uracil 400 mg/m2/day with leucovorin was feasible, but did not meet the expected pathologic complete response rate. The UMPS 638 CC genotype might be a candidate biomarker predicting toxicity in patients receiving tegafur-uracil/leucovorin-based preoperative chemoradiation for locally advanced rectal cancer. ISRCTN11812525 , registered on 25 July 2016. Retrospectively registered.

We performed laboratory experiments to investigate the response of Fragilariopsis kerguelensis, a predominant diatom species in the Southern Ocean, to different concentrations of dissolved iron in the culture medium to assess changes in nutrients, trace metals, and greenhouse gases-CO2, CH4, and N2O-during growth. F. kerguelensis was cultured in standard f/2+Si media contained in closed chambers at 2℃, which is a typical surface temperature of the Southern Ocean in summer, under continuous irradiation with ~44 μmol photons m-2 s-1 for 8 days. The media contained 2.2 nM, 7.0 nM, and 10.6 nM of dissolved iron at inoculation. F. kerguelensis grew faster if the initial dissolved iron concentration was higher. Its production rate was ~40 cells mL-1 d-1 with an increase of 10–18 molar dissolved iron on a single cell basis. Fe and Mo were consumed faster than the growth rate at higher dissolved iron concentrations while Mn and Zn were consumed more slowly taking the mean values into account. Nitrate consumption by single cells increased with an increase of dissolved iron in the media, but phosphate and silicate showed a tendency to decrease. Hence, dissolved iron enhanced uptake of nitrate, but not the other nutrients, on a single cell basis. The carbon uptake per cell decreased with an increase in dissolved iron, which is opposite to the growth rate, suggesting that carbon content in single cells could not keep up with the cell growth. The iron efficacy of carbon uptake by single cells, defined as the ratio of the carbon uptake to the iron uptake, also showed a significant reduction with an increase in dissolved iron. This implies the inefficient usage of iron to absorb carbon at a high dissolved iron concentration. CH4 uptake by F. kerguelensis occurred in our experiments, but it was trivial in relation to the overall impact. N2O was consumed at a lower concentration of dissolved iron, but was emitted at a higher dissolved iron concentration, suggesting a facultative response of F. kerguelensis to the available dissolved iron.

To perform chemoradiotherapy (CRT) effectively, it is clinically beneficial to identify predictors of tumor response after CRT. This study examined the association between plasma fibrinogen level before preoperative CRT and tumor response in advanced rectal cancer. This was a retrospective study of 947 patients who received preoperative CRT followed by curative surgery for primary rectal cancer. We analyzed clinical factors that could be associated with pathologic tumor response in terms of downstaging (ypStage 0-I), primary tumor regression (ypT0-1), and complete response (ypT0N0). Downstaging was observed in 366 patients (38.6%), primary tumor regression in 187 patients (19.7%) and complete response in 138 patients (14.6%). Multivariate analysis found that pre-CRT carcinoembryonic antigen (CEA) level, fibrinogen level, hemoglobin level, clinical T and N classification, distance from anal verge, and histologic grade were significant predictive factors for downstaging; CEA level, fibrinogen level, and N classification predicted primary tumor regression; CEA level, and fibrinogen level were predictive for complete response. This study demonstrated that fibrinogen level was a significant predictor of pathologic tumor response after preoperative CRT.

In this work, the effect of initiator diol-BF3 complex solubility on an induction period was investigated for BF3 catalyzed cationic ring opening polymerization of epichlorohydrin at various [BF3]/[initiator diol] ([C]/[I]) ratios, using on-line temperature and torque monitoring systems. Other factors influencing the induction period (reaction temperature: −5∼30 °C, [C]/[I] ratio, and monomer feed rate: 9.2×10−3–27.6×10−3 mol·min−1) were also investigated in order to optimize the polymerization condition in the presence of the diethylene glycol (DEG)-BF3 complex. A 5-L, triple-glass jacket reactor was customized for the monitoring system. 1,4-Butanediol (BD) and diethylene glycol (DEG) were used for the initiator diol. In the presence of the BD-BF3 complex, which is insoluble in methylene chloride solvent (MC), an uncontrollable and highly exothermic reaction occurred shortly after the long induction period. Although there was an induction period with the DEG initiator diol, the exothermic reaction which followed was much more controlled, and the resulting polymers showed relatively narrow polydispersities (1.31–1.34) using the DEG initiator diol, which is soluble in MC. The longer induction period, which was highly affected by the solvation effect of the reaction media, appeared at a lower reaction temperature and [C]/[I] ratio. The molecular weights and structural characterizations of PECHs were analyzed via GPC, 1H-NMR.